Project Summary Total knee arthroplasty (TKA) is currently the most common elective surgery in the US and will increase in frequency nearly five-fold by 2030 to 3.5 million surgeries annually. This surgery is most prevalent among older adults with advanced knee osteoarthritis (OA) and its increase is explained primarily by growth in this population. Although TKA reliably reduces joint pain, it fails to correct objectively-measured functional disability due, in part, to dramatic declines in lower-extremity neuromuscular function during the early, post- surgical period. These deficits are never fully remediated, remaining for years after surgery and contributing to persistent disability. Despite these detrimental effects of TKA, the fundamental skeletal muscle adaptations that occur in the early, post-surgical period are poorly defined and understudied and there is currently no widely-accepted, evidence-based intervention to counter these changes. To address this clinical problem, our goals in this application are to define the skeletal muscle structural and functional adaptations following TKA at the whole body, tissue, cellular, organellar and molecular levels in humans in an effort to identify factors contributing to functional disability and to assess the utility of neuromuscular electrical stimulation (NMES) to counter post-surgical muscle adaptations at these same anatomic levels. Based on our preliminary data, we propose a hypothetical model in which TKA fails to remediate physical disability in patients, in part, because of the profound skeletal muscle myofilament and mitochondrial loss and dysfunction that develops during the early, post-surgical period. Moreover, we posit that NMES will improve functional recovery following TKA by countering these early skeletal muscle adaptations. To test this model, we will evaluate knee OA patients prior to and following TKA for skeletal muscle structure and function at multiple anatomic levels, with patients randomized to receive NMES or sham control intervention during the first 5 weeks post-surgery. We anticipate that our results will yield seminal, mechanistic knowledge of the early, post-surgical skeletal muscle structural and functional adaptations to TKA, which will challenge conventional thinking in this field and provide novel targets for rehabilitative and pharmacological intervention. Additionally, our results will provide mechanistic evidence for the utility of NMES to prevent deleterious post-surgical adaptations in skeletal structure and function. Our findings, therefore, hold the potential to advance both basic scientific knowledge and clinical practice towards the goal of improving long- term functional and health outcomes in knee OA patients, the most disabled sector of the older adult population.